Seropositive rheumatoid arthritis /RA/ is a chronic inflammatory disease involving synovium. Rheumatoid nodules and synovitis of RA respond differently to methotrexate /MTX/ treatment. In 8% of patients started on MTX, accelerated nodulosis and/or vasculitis develop, while synovitis improves. The hypothesis is that rheumatoid synovitis and rheumatoid nodules are characterized by distinct cytokine profiles, reflecting the predominant active T cell population in each site. MTX may selectively influence TH2 derived cytokines in synovial tissue, but not TH1 T cells in rheumatoid nodules. We will analyze cytokine profiles in peripheral blood, nodule tissue, synovial fluid, and synovial tissue before initiation of therapy and 6-8 weeks after therapy. We will directly examine expression of the cytokine genes by semiquantitating the relative amounts of mRNA for the cytokine gene products evident in each sample. To study possible mechanisms, we will examine the in vitro effect of MTX on TH1-like and TH2-like T cell clones. From this study, we hope to gain insight into the pathogenic process underlying RA, as well as into the mechanism of action of this relatively commonly used drug.